pine Dose Response Relationship in.4[1]

8/6/2019 pine Dose Response Relationship in.4[1]

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CNS Drugs 2008; 22 (1): 49-68REVIEW ARTICLE 1172-7047/08/0001-0049/$48.00/0

2008 Adis Data Information BV. All rights reserved.

QuetiapineDose-Response Relationship in Schizophrenia

Anna Sparshatt, Sarah Jones and David Taylor

Pharmacy Department, Maudsley Hospital, Denmark Hill, London, England

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

1. Fixed-Dose Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

2. Flexible Dosage within Fixed-Dose Range Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

3. Variable-Dose Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

4. Single Fixed-Dose Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

5. Neuroimaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

6. Case Series and Cohort Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

7. Review Articles and Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

8. Effectiveness Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Quetiapine is a widely used second-generation antipsychotic that is effective inAbstractthe treatment of schizophrenia and bipolar mania. In recent years, various publica-

tions have suggested the possibility that, in some patients, higher than licensed

dosages are necessary for full therapeutic effect. A high-dose theory of que-

tiapine activity has developed, leading many prescribers to disregard the formal

upper limit of the quetiapine dosage range (750 or 800 mg/day, depending on local

labelling).

In this review, we examine the clinical and neuroimaging data relating to the

use of quetiapine in acute exacerbations of schizophrenia. Fixed-dose efficacy

studies of immediate-release (IR) quetiapine suggest dosages of quetiapine of

150450 mg/day are more effective than placebo and no less effective than

dosages of 600 or 750 mg/day. A fixed-dose study of extended-release quetiapine

indicated that dosages of 600 and 800 mg/day were equally efficacious and

numerically superior to 400 mg/day. Dosages of IR quetiapine averaging between

254 and 525 mg/day have been shown to be equivalent in efficacy to standard

dosages of conventional and other atypical antipsychotics. Pooled data support

these findings. Effectiveness studies using quetiapine in daily doses averaging

between 565 and 653 mg revealed quetiapine to be somewhat less effective than

some comparator drugs.


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50 Sparshatt et al.

Support for the use of high-dosage quetiapine (>800 mg/day) is very limited:

case reports, albeit numerous, describe quetiapine as showing therapeutic effects

only at dosages above the licensed range; some data suggest widespread use ofhigher dosages in practice; and neuroimaging data suggest inadequate dopamine

receptor occupancy at standard dosages (although these findings may reflect the

low affinity of quetiapine for dopamine receptors).

Overall, robust controlled data strongly suggest that the standard dosage range

for quetiapine is appropriate for clinical use. The balance of evidence does not

support the belief that higher dosages are required for full therapeutic effect,

although higher dosage trials are ultimately required to confirm or refute this

hypothesis.

Quetiapine is an effective and widely used vealed all relevant reports published in any form.

second-generation antipsychotic. In recent years, We were not able to obtain any unpublished or data

doubts about the appropriateness of its licensed dos- on file reports.

age range for acute exacerbations of schizophrenia

have been expressed, largely on the basis that the 1. Fixed-Dose Trialsofficial maximum dosage (750 or 800 mg/day, de-

pending on local labelling) is frequently exceeded in Trials in which subjects are randomly assigned to

practice.[1] Higher than maximum dosages have also single fixed doses of a drug provide the most robust

been used in refractory schizophrenia[2]

and non- evidence of dose-response relationships, assumingschizophrenic disorders.[3] Such dosages are report- that studies recruit sufficiently large numbers of

edly well tolerated,[2,4] although unexpected adverse patients to reveal true differences and include a

events are occasionally reported.[5] sufficiently wide range of doses.

The possibility that the licensed dosage range for A single study of multiple, active fixed dosages

quetiapine does not include optimal dosages for of immediate-release (IR) quetiapine has been re-

some patients has important consequences, both ported.[6] In this trial, subjects with an acute exacer-

clinical and pharmacoeconomic. This review exam- bation of schizophrenia were randomized to one of

ines published data relating to the dose-response five dosages of quetiapine, placebo or haloperidol

relationship for quetiapine in acute exacerbations of 12 mg/day and evaluated over 6 weeks. Outcome

schizophrenia. was assessed by changes in Clinical Global Impres-

In January 2007, we searched EMBASE and sion-Severity of Illness (CGI-S)[7] score and Brief

MEDLINE using the terms quetiapine, schizo- Psychiatric Rating Scale (BPRS)[8] score (table I).

phrenia, dose, placebo, trial, efficacy and effective- The outcome was almost identical for quetiapine

ness. All relevant references were obtained in full (150, 300, 600 and 750 mg/day) and haloperidol. All

and reference sections of each scrutinized for rele- treatments other than quetiapine 75 mg/day were

vant citations. We selected for review those reports significantly more efficacious than placebo. There

describing the clinical evaluation of quetiapine in was no obvious trend for response to improve over

acute exacerbations of schizophrenia. In July 2007, the quetiapine dosage range of 150750 mg/day on

the search was repeated and AstraZeneca in the UK either clinical outcome scale, with numerically thewas contacted to confirm that our search had re- greatest change in mean BPRS score being seen at

2008 Adis Data Information BV. All rights reserved. CNS Drugs 2008; 22 (1)


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Dose-Response Relationship of Quetiapine in Schizophrenia 51

quetiapine 150 mg/day. Logistic regression failed to

demonstrate a predictive relationship between dos-

age and response.A second fixed-dose study compared three daily

doses (400, 600 and 800 mg) of quetiapine extend-

ed-release (XR) with one daily dose of quetiapine IR

(400 mg) and placebo (table I).[9] All active treat-

ments were significantly more effective than place-

bo, as assessed by the Positive and Negative Syn-

drome Scale (PANSS),[10] but change in score was

greatest with dosages of 600 and 800 mg/day. There

was no direct statistical comparison of one dosageagainst another, but post hoc analysis of PANSS

change for increasing dosages indicated a signif-

icant dose-response relationship (p = 0.013; calcu-

lated by the Jonckheere-Terpstra test[11]). In addi-

tion, quetiapine XR 400 mg/day failed to separate

from placebo on one primary outcome measure

(CGI-S). Response rates (defined as a 30% reduc-

tion in PANSS score) were 30.4% for placebo,

44.1% for quetiapine XR 400 mg/day, 60.4% for XR

600 mg/day, 56.4% for XR 800 mg/day and 52.9%

for quetiapine IR 400 mg/day. All active treatments

were statistically superior to placebo on this mea-

sure.

Two further fixed-dose studies have compared

three dosage regimens (two effective daily doses

and one assumed to be inactive) of IR quetiapine

over 6 weeks (see table II).[12,13] In both studies

subjects were randomized to 25 mg twice daily,

225 mg twice daily or 150 mg three times daily. In

the larger of these trials, efficacy was measured

using several rating scales, outcomes for which are

shown in table II.[12] In both 450 mg/day groups,

scores improved from baseline when compared with

the 50 mg/day group, as measured using the BPRS,

but with no difference between these two higher

dosage groups. However, no statistically significant

difference was observed in the proportion of re-

sponders (defined as those patients with at least a30% reduction from baseline in BPRS total score at


Table

I.Multiplefixed-dosestudies,vsplace

boandhaloperidol

Study

design

Subjects

No.of

Exclusioncriteria

Treatmentanddosage

Outcom

e(endpointmeanchangefrom

Reference

subjects

[mg/day](n)

baseline)

CGI-Se

verity

BPRStotal

PANSS

ofIllnes

s

score

totalscore

6-wk,

randomized,

Hospitalizedpatients,

361

OtherAxisIDSM-III-R

Placebo(51)

0.25

0.15

1.712.06

NA

6

double-blind,placebo-

1865yofagewith

diagnoses

QuetiapineIR75(53)

0.15

0.15

2.242.04

NA

contro

lled,multicentre

adiagnosisof

QuetiapineIR150(48)

0.49

0.16**

8.672.14**

NA

schizophrenia

QuetiapineIR300(52)

0.69

0.15**

8.592.06**

NA

QuetiapineIR600(51)

0.46

0.16**

7.682.08**

NA

QuetiapineIR750(54)

0.46

0.15**

6.332.02*

NA

Haloperidol12(52)

0.69

0.16

7.582.10**

NA

6-wk,

randomized,

In-oroutpatients,

573

OtherAxisIDSM-IV

Placebo(115)

1.0

NA

18.8

9

double-blind,placebo-

1865yofagewith

diagnosis,substance

QuetiapineXR400(111)

1.3

NA

24.8*

contro

lled,multicentre

adiagnosisof

misuse,hospitalization


1.5**

NA

30.9**

schizophrenia

for>1mo,treatment


1.6**

NA

31.3**

resistance,priordepo

t

QuetiapineIR400(119)

1.3*

NA

26.6**

antipsychoticwithin

onedosinginterval

BPRS

=BriefPsychiatricRatingScale;CGI=

ClinicalGlobalImpressionscale;IR=immediaterelease;NA

=notapplicable;PANSS=PositiveandNegativeSyndromeScale;

XR=

extendedrelease;*p65% when showing anti-and 375 mg twice daily, having not responded to

psychotic activity.[32] Dosages of quetiapine rangedseveral previous antipsychotics each and experienc-

from 150 to 750 mg/day. The most recent studying years of illness. These case reports support the

showed that D2 receptor binding of quetiapine va-findings of the single fixed-dose study already dis-

ried according to the brain area examined (lowest incussed, indicating a possible role for quetiapine in

the putamen, highest in the temporal cortex [33.5%treatment-resistant schizophrenia.

vs 46.9%]).[33]

5. Neuroimaging Studies6. Case Series and Cohort Studies

Neuroimaging techniques such as positron emis- A 15-month open-label, variable-dose study

sion tomography (PET) and single photon emission examined 35 patients with a diagnosis of schizo-

computerized tomography (SPECT) have been ap- phrenia or other psychotic disorder.[36] Patients re-

plied to the use of quetiapine in humans. These trials ceived quetiapine at starting dosages of 100 or 400

were designed to estimate the dopamine receptor mg/day, titrating upwards by 50100 mg/day every

occupancy of quetiapine. Although a secondary con- 12 days to a maximum daily dose of 1600 mg. The

sideration, some studies showed improvement in modal dosage used was 800 mg/day, with 12 pa-clinical efficacy measures for quetiapine across dif- tients prescribed >1000 mg/day for an average of



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58 Sparshatt et al.

4 weeks, before decreasing to a maintenance dosage

of 200600 mg/day. Statistical analysis was not

reported; however, the study showed that at4 weeks, 94.3% of subjects had shown an improve-

ment in global symptoms, and an improvement was

seen in all subjects who received >800 mg/day. A

rapid response was reported in terms of a decrease in

hostility, restlessness and insomnia at days 13,

irrespective of the initial dosage. Hallucinations

were reported to improve after 1 week and delusions

improved after 3 weeks, although dosages >800 mg/

day were reported to be necessary to eliminate thesesymptoms.

There are a number of single case reports in the

literature. The first of these described rapid dose

escalation of quetiapine to 600 mg by day 7 of

treatment in a 34-year-old male with a diagnosis of

treatment-resistant schizophrenia that had been

treated with zuclopenthixol decanoate 200 mg

weekly immediately before quetiapine.[37] Baseline

PANSS total score fell from 90 to 60 by day 77during the study period. Symptoms of tardive dys-

kinesia also improved during this time, as deter-

mined by an improvement in adverse effects on the

Abnormal Involuntary Movement Scale (AIMS),[38]

with a fall from a score of 21 at baseline to 2 at

day 77.

A further case study reported the use of high-dose

quetiapine, up to 1000 mg/day, in a 12-year-old

male with conduct disorder and attention-deficit

hyperactivity disorder.[39] Minimal improvement in

symptoms had previously been seen in response to

stimulants, lithium and olanzapine 15 mg/day. No

improvement in symptoms was seen at a dosage of

quetiapine of 300 mg/day, but once increased to

1000 mg/day (400 mg in the morning and 600 mg at

night) a dramatic improvement in his psychiatric

symptoms was reported. At day 90, the patient

continued to be maintained at 1000 mg/day with noadverse effects reported.


Table

VI.Singlefixed-dosestudy

Study

design

Subjects

No.of

Exclusioncriteria

Druganddosage

Outcome

[endpointmeanchangefrom

Reference

subjects

[mg/day](n)

baseline]

PANSStotal

BPRStotal

CGI-Severity

score

score

ofIllness

8-wk,

international,

Male/femaleoutpatients

281

Treatment-resistant

Quetiapine600(140)

11.50

6.95

0.53

27

randomized,double-

>18yofagewitha

schizophrenia,

Haloperidol20(141)

8.87

4.78

0.38

blind,

multicentretrial

diagnosisof

clozapine

(p=0.234)

(p=0.105)

(p=0.221)

schizophrenia

nonresponders,acute

exacerbationof

schizophreniainlast

3mo

BPRS

=BriefPsychiatricRatingScale;CGI=ClinicalGlobalImpressionscale;PAN

SS=PositiveandNegativeSyndrome

Scale.


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A commentary article discussed clinical experi-


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60 Sparshatt et al.


Table

VII.Neuroimagingstudies

Study

designandmethod

Subjects

No.of

Exclusioncriteria

Clinicalefficacy

PET/SPECTresultsandplasma

Reference

subjects

measures

concentrations

meanD2receptor

plasma

occupancy[%]

concentration

(range)

1-wkescalationto150mgtid,then

Male,D

SM-III-R

8

Nootherantipsychotics

Nosystematicratings/

44(2168)at2h

402.8at2hand

29

fixeddosageof450mg/dayfor

diagnosisof

andnodepot

clinicalmeasuresused.

27(654)at12h

7.2at26ha

29days.FourPETscansover

schizop

hrenia

antipsychoticfor2

mo

Atday14,eightsubjects

26-hp

eriodafterwithdrawal

beforetrialperiod

remainedinthetrialwith

goodsymptom

controland

allclinicallyimprovedon

fixeddoseof150mgTDS

Dosag

esof150mg/day(n=3),

Aged1

845y,

15

Noothermajorillness

PANSS

12hpostdose:

12hpostdose:

30

300m

g/day(n=3),450mg/day

DSM-IV

orsubstancemisu

se.

Baselinemean:62.8

1

7.1

150mg/day=

150mg/day=

(n=3

),600mg/day(n=3),not

diagnosisof

Nodepotantipsyc

hotics

Wk1012:52.9

2

4.4

22

294ng/mL

completed(n=3).Dosesheldthen

schizop

hrenia

withinlast12mo

(p=0.007)

300mg/day=

300mg/day=

PETs

canatdays21and28,then

CGI

57

502

8ng/mL

flexibledosing(range150600mg/

Baselinemean:4.2

0.7

450mg/day=

450mg/day=

day)for8wk

Wk1012:291.7

141

1

1721

11ng/mL

(p=0.001)

600mg/day=

600mg/day=

191

2011

13ng/mL

(p=0.008,

dose/plasma

concentration

correlation)

Patien

t1

3wkhaloperidol20mgIM

every

Male,3

3yof

1

NA

PANSStotal

Day1:94

NA

34

3wk,

thenoralhaloperidol15mg/

age,DSM-IV

Day1:98

Day21+:76

dayfo

r20wk,thenquetiapine750

diagnosisof

Day21:100

mg/da

yfor2wk.SPECTonday1

schizop

hrenia

CGI

ofswitchandthenonday21

NA

Patien

t2

Zuclopenthixol200mgonce

Male,3

4yof

1

PANSStotal

Day14:51

NA

weeklyfor6mo.5-wkbreakthen

age,DSM-IV

Day14:67

Day90:28

quetia

pine600mg/dayfor90days.

diagnosisof

Day90:60

SPEC

Tscandays14and90

schizop

hrenia

CGI

NA

Continuednextpage


13/20


14/20

62 Sparshatt et al.

gate markers. A series of trials reported during

20052006, known as the CATIE (Clinical Anti-

psychotic Trials in Intervention Effectiveness)trials,[45-47] compared the efficacy of several antipsy-

chotics. In the first phase of the study,[45] olanzapine,

quetiapine, risperidone and ziprasidone, as well as

the typical antipsychotic perphenazine, were com-

pared in patients with chronic schizophrenia

(n = 493). Dosages of quetiapine used were in the

Table VIII. Pooled data from long-term extension studies[42]

Timepoint BPRS total score CGI-S score

(mean dosage (mean dosage

439.5 mg/day) [n] 438.5 mg/day) [n]Baseline 40.67 (95% CI 39.44, 4.81 (95% CI 4.73, 4.90)

41.90) [258] [259]

6 wk 13.94 (95% CI 12.93, 3.00 (95% CI 2.88, 3.11)

14.95) [258] [259]

156 wk 9.04 (95% CI 4.62, 13.46) 2.43 (95% CI 1.92, 2.95)

[24] [23]

BPRS = Brief Psychiatric Rating Scale; CGI-S = Clinical Global

Impression Scale-Severity subscale.

range of 200800 mg/day, with a mean modal dos-

age of 543.4 mg/day. At 18 months, 18% of subjectsphrenia.[44] The results of previously included trialswho had been prescribed quetiapine remained on

are discussed to support the use of quetiapine in the this treatment, while 21%, 25%, 26% and 36%early stages of schizophrenia.[6,15,18] Case reports are

remained on ziprasidone, perphenazine, risperidonealso included in order to report the successful treat-

and olanzapine, respectively. The difference in timement with quetiapine of two patients in the early

to discontinuation between quetiapine and olanza-stages of their illness. Dosages used were 300 and

pine was statistically significant (p = 0.001), but it600 mg/day, with symptoms resolving in both cases.

should be noted that the mean dosage of olanzapineA review article, based on a PubMed search to

administered was above the licensed maximum forobtain all articles related to high-dose quetiapinethis drug (20 mg/day).use, discussed the high dosages of quetiapine used in

clinical practice.[1] This was reported alongside a Further to this phase, subjects who discontinueddiscussion of trends in dosing in a large state hospi- in the first stage were then re-randomized to a differ-tal in the US. The mean dosage used in this hospital ent drug from the above antipsychotics, excludingwas 620 mg/day, but patients who were non-White, perphenazine (n = 444).[47] Quetiapine was used inwith admission of >1 year and prior admission his- dosages of 200800 mg/day (n = 63). Again, effi-tory were more likely to receive >750 mg/day cacy was measured by time to discontinuation. The(p < 0.05). Dosages in excess of 1200 mg/day were time to discontinuation was longer for subjects tak-also being used. The efficacy of these high dosages ing risperidone (median 7.0 months) and olanzapineis not described and the trials reported on in the (6.3 months) than those taking quetiapine (4.0review have been discussed previously.[6,15,22] months) and ziprasidone (2.8 months). In those who

discontinued their previous treatment in stage 1 be-8. Effectiveness Studies cause of inefficacy (n = 184), olanzapine was shown

to be more effective than quetiapine and ziprasi-

Effectiveness studies examine the use of drugs in done, and risperidone was shown to be more effec-

comparatively naturalistic settings and compare tive than quetiapine, as measured by median time to

drugs using pragmatic outcomes rather than surro- discontinuation for any reason. Changes in PANSS

Table IX. Pooled data from open-label studies (reproduced from Kasper et al.,[43] with permission)

Rating scale Week 26 (n = 305) Week 104 (n = 86) Week 208 (n = 39) p-Value (vs baseline)

BPRS total: difference from baseline 15.8 15.7 25.6 12.6 27.5 19.0 0.001

CGI-S: difference from baseline 1.2 1.5 2.1 1.4 2.4 1.6 0.001BPRS = Brief Psychiatric Rating Scale; CGI-S = Clinical Global Impression Scale-Severity subscale.



15/20


scores showed improvement to be significantly

greater in the olanzapine group than the quetiapine

group (estimated mean difference 6.8; SE = 2.4;p = 0.005) and the ziprasidone group (difference

5.9; SE = 2.1; p = 0.005), but not in the risperidone

group.

Another arm of the study compared subjects with

treatment-resistant symptoms who had discontinued

in the initial trial and were then randomized to

clozapine, olanzapine, risperidone or quetiapine.[46]

The mean modal dosage of quetiapine used was

0

75

150 300 600

750

25

20

15

10

5

5

00 100 200 300 400 500 600 700 800

Quetiapine fixed dosage (mg/day)

ChangeinBPRSscor

e(%)

(Placebo)

Fig. 1. Quetiapine fixed-dose vs response. BPRS = Brief Psychiat-

ric Rating Scale.642.9 mg/day. Again, differences were seen in time

to discontinuation, with clozapine being significant-its slope dictates dosing strategies in clinical prac-ly superior to quetiapine (p = 0.01) and risperidonetice. For some drugs the slope is nearly vertical, such(p < 0.02) but not olanzapine. When reporting num-that once a threshold dosage is reached almost all ofbers of subjects withdrawing from the study becausethe clinical effect is seen (examples include parace-of lack of efficacy, clozapine was superior to olanza-tamol [acetaminophen] and thiazide diuretics).pine (p < 0.02), quetiapine (p = 0.004) and risper-Where the slope tends more towards the horizontalidone (p = 0.003).there is greater opportunity to increase dosage for a

In the most recent effectiveness study, quetiapinegradually greater effect; good examples here are

was compared with five other antipsychotics in a

morphine and furosemide (frusemide) therapeuticrandomized naturalistic evaluation of patients hospi-effects increase over a wide dosage range. Evidencetalized with relapsed schizophrenia (n = 327).[48]

relating to antipsychotics strongly suggests a thres-Quetiapine was found to be significantly less effec-hold-type relationship; all studied drugs show a

tive than haloperidol (89% no longer required hospi-near-vertical linear portion of the dose-response

tal care), olanzapine (92%) and risperidone (88%).curve[49] and threshold dosages are reasonably well

In the quetiapine group, 64% of subjects still re-established for drugs such as risperidone (4 mg/quired hospital treatment at endpoint (p < 0.0001);day)[50] and haloperidol decanoate (100 mg/

mean dosage was 652.5 mg/day (up to 1200 mg/daymonth).[51] These threshold dosages are also the

was allowed).dosages at which maximal effect is seen; dosage

increases provide no additional effect.9. ConclusionGiven the uniformity of the shape of anti-

Before discussing the data presented in this re- psychotic dose-response relationships, one might

view, it is worth first considering the nature of the expect quetiapine to show similar properties. Dose-

dose-response relationship seen with antipsychotic response curves are usually drawn from data derived

drugs. For all drugs there will be low dosages that from fixed-dose clinical trials. When a curve is

provoke no therapeutic effect and higher dosages drawn using the major fixed-dose study of IR que-

beyond which no further effect is seen. In between tiapine[6] (figure 1), the curve demonstrates a near-

these extremes, successively larger dosages give rise vertical linear portion, with the threshold dosage at

to successively larger effects. This is the so-called 150 mg/day. There is no additional benefit fromlinear portion of the (s-shaped) dose-response curve; using 600 or 750 mg/day. In fact, a change in



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64 Sparshatt et al.

symptom scores is numerically less at these higher this trial strongly suggests, given its power to show

differences, that no further benefit is likely to bedosages. Of course statistical power considerations

seen at dosages >600 mg/day, at least in anti-are important here; the study may not have hadpsychotic-responsive patients such as those recruit-sufficient statistical power to reveal small or even

ed into the study.moderate differences in outcome and, given the

small number of subjects and high rate of dropout, Taken together, these two major fixed-dose stud-confidence intervals for each dosage are likely to be ies do not suggest that dosages above the licensedvery wide. Notably, however, if 150 and 300 mg/day dosage range are likely to offer increased efficacy;subject groups are combined and compared with the however, no certainty can be expressed on this issuetwo higher-dosage groups combined (thereby in- since there are no evaluations of fixed dosagescreasing study power), the lower-dosage group is >800 mg/day. It is possible (although unlikely givennumerically superior, hence ruling out any possibili-

the results of the two studies conducted) that dos-ty of there being statistically significant advantage ages of, say, 1000 or 2000 mg/day provide betterfor the higher-dosage group. This suggests only efficacy than lower licensed dosages. Without ro-a very remote possibility of dosages higher than bust evaluations of dosages of this magnitude it is300 mg/day offering increased efficacy, and even impossible to rule out this possibility.then differences are likely to be small. Also of note

Studies using fixed ranges of quetiapine dosageshere is the observation that analyses of pooled data

are relatively less informative about dose-responsehave failed to demonstrate advantages to higher

relationships but are helpful in some respects. In thedosages.

largest of these studies, a mean dosage of quetiapine

Nonetheless, these analyses of pooled data did 209 mg/day was not superior to placebo and wasnot include results from the fixed-dose study of clearly inferior to a mean dosage of 360 mg/day.[15]

quetiapine XR.[9] This comparatively large study This suggests a different threshold for effect to that

gives a somewhat different view of the dose-res- already described one >209 mg/day (although

ponse relationship of quetiapine. Dosages of que- excluding those on 400 that researchers abandoned treatment before trying

mg/day (as suggested by occasional poor results higher dosages, as evidenced by the high dropoutrates in some studies). This pattern of prescribingseen with dosages around this value[18]); however,



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tentatively suggests that dosages around 300400 tionships established in these patients do not reflect

mg/day were observed to be acceptably therapeutic; those in substance or alcohol misusers (typical pa-

there was no clear escalation of dosages in search of tients in many areas) in whom higher dosages mighteffect. Contrast this to the lower dosage group in be required. Conversely, most trials recruited relap-

which the average dosage used approaches the max- sed and acutely ill, hospitalized patients who might

imum allowable dosage, reflecting dosage escala- be said to be more likely to require higher dosages

tion towards the maximum allowable dosage in than, say, outpatients or first-episode patients. These

search of efficacy. two competing influences may balance out overall

the established optimal dosage for risperidone inVariable-dose studies are informative on a simi-non-alcohol/substance misusing hospitalized pa-lar basis; the difference between the mean dosagetients[50] is similar to the average dosage used inused and the maximum allowable dosage offerspractice.[52] Also of note is the recruitment in most

reassurance (or otherwise) that the true optimal dos- trials of subjects known to be responsive to treat-age is within the dosage range allowed, notwith-ment. Effective dosage ranges may well be differentstanding the possibility that tolerability or otherin refractory illness.problems constrain dosage increases. In one study. a

mean dosage of 307 mg/day did not separate from Effectiveness data from the CATIE trials do littleplacebo, but dosages of 750 mg/day were al- to support the high-dose theory for quetiapine. Inlowed.[18] Other studies were more successful: a largely responsive (i.e. not clearly treatment resis-mean dosage of 455 mg/day was equivalent to halo- tant) patients[45,47] quetiapine dosages averaging be-peridol 8 mg/day;[19] a mean dosage of 254 mg/day tween 500 and 600 mg/day were used (titration towas equivalent to risperidone 4.4 mg/day;[20] a mean

800 mg/day was allowed). Although such dosagesdosage of 525 mg/day was broadly equivalent to proved relatively less effective than some other anti-risperidone 5.2 mg/day;[21] and a mean dosage of psychotics (in the case of olanzapine, administered407 mg/day was equivalent to chlorpromazine at higher than licensed dosages) there was no clear384 mg/day.[22] In each study the maximum allowa- pressure on dosing in the search for efficacy. Inble dosage was 750 or 800 mg/day. None of these patients with treatment-resistant symptoms,[46] thestudies suggest that the licensed range of dosages is mean modal dosage of 642.9 mg/day does suggestinsufficient or inadequate in any way there was no dosage increases in the search for effect. Despite thispressure on the maximum dosage in search of high average dosage, quetiapine was found to beefficacy. Moreover, if quetiapine is equivalent to inferior to several comparators. In the effectiveness

comparator antipsychotics at mean dosages ranging study of McCue and colleagues,[48] a mean dailyfrom 254 to 525 mg/day then, if the high-dose dose of 652.5 mg was inferior to comparator drugs,theory is to be accepted, higher dosages are likely to and dosages of up to 1200 mg/day were allowed.be superior to standard antipsychotics, an unlikely These effectiveness data appear to suggest that que-proposition, but one which cannot be discounted in tiapine itself is rather less effective than some otherthe absence of robust high-dose studies. antipsychotics. It might be argued, however, that

restricting the dosage to 800 mg/day (or even 1200A further consideration is the type of patient

mg/day) unfairly constrained clinicians in seeking torecruited into trials, particularly strictly controlled

gain the optimal effect from the drug. Nonetheless,efficacy studies. Many trials, for example, excluded

as already seen, the fact that mean dosages usedsubjects with a history of misuse of alcohol or elicitwere substantially below the maximum allowablesubstances. It is possible that dose-response rela-



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66 Sparshatt et al.

dosage militates against this proposition, although it ligand).[54] (This fast-dissociation theory has been

put forward by Kapur and Seeman[32]).remains possible, if unproven, that higher dosages

might be needed in patients with refractory symp- Considering together all the data presented in thistoms. Note, however, that in patients with partially review, it can be seen that there is substantial, if

resistant symptoms[27] a dosage of 600 mg/day inconclusive, evidence that the optimal dosage of

seemed adequate. quetiapine is within the range 150800 mg/day, with

most data pointing towards an optimal dosage ofThe case studies and series cited in this review

around 300400 mg/day and some very cogent datado, of course, suggest that higher dosages of que-

suggesting that slightly higher dosages (at least oftiapine (often >1000 mg/day) can be effective where

the XR preparation) are optimal. In contrast, therelower dosages from the licensed dosage range have

are no scientifically robust data suggesting that dos-failed. It would be wrong to doubt the veracity of

ages higher than the licensed range provide im-these reports but one should bear in mind the uncon- proved response or other clinical benefits. In fact,trolled, open nature of these mini trials, and also

studies using higher mean dosages tend to showconsider the probable reluctance of journals to pub-

quetiapine to be inferior to comparator drugs. Evi-lish and authors to submit reports of the failure of

dence suggesting improved response at higher dos-high-dosage quetiapine treatment (about whose ex-

ages is limited to uncontrolled case reports of pa-istence we can say nothing). One important observa-

tients with treatment-resistant schizophrenia and is,tion, however, is that high dosages seem to be well

on a theoretical basis, supported only by an uncon-tolerated, indicating that tolerability is unlikely to be

ventional interpretation the results of receptor occu-a constraining influence on dosages in clinical trials.

pancy studies. The balance of probabilities indicate

Dopamine receptor occupancy studies of que- that the current licensed dosage range for quetiapinetiapine have produced perplexing results. Measured is appropriate, but fixed-dose studies of dosagesmean striatal D2 occupancies range from 2% at above the licensed range are required before the full150 mg/day[30] to 62% at 750 mg/day.[31] In the latter dose-response relationship for quetiapine can bestudy, responders had significantly higher mean firmly established.peak occupancies (65.9%) than nonresponders

(60.3%). Thus, neuroimaging data suggest unusual-Acknowledgements

ly low receptor occupancies for quetiapine, i.e. oc-

cupancies generally below the suggested thresholdNo sources of funding were used to assist in the prepara-

of that required for response (65%).[53] The observa-tion of this review. Professor Taylor has received con-tion that mean occupancy of 65.9% produced a sultancies fees, lecturing honoraria and/or research funding

response where lower occupancies did not show any from AstraZeneca, Janssen-Cilag, Servier, Sanofi-Aventis,Lundbeck, Bristol-Myers Squibb, Novartis, Eli Lilly andeffect could be taken as evidence that higher dos-Wyeth. He has also received royalties from Gaskell andages are required for effect (these occupancies wereInforma Healthcare. Ms Sparshatt and Ms Jones have no

achieved at a dosage of 750 mg/day). However,conflicts of interest that are directly relevant to the content of

lower occupancies were shown to be effective in this review.other studies[29,30,35] and, perhaps more importantly,

measured D2 receptor occupancies are thought to atReferencesleast partly reflect competition for receptor sites

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